Plasma concentrations of tenofovir alafenamide AUC were decreased by 55% and intracellular tenofovir-diphosphate concentrations by 36% when given with rifampicin. But intracellular concentrations were still 76% higher than those with standard dose tenofovir disoproxil fumarate.1

These data from RIFT, a pharmacokinetic (PK) study of once-daily tenofovir alafenamide (TAF) with rifampicin (RIF) conducted by Maddalena Cerrone and colleagues from Chelsea and Westminster Hospital, London, UK, The Johns Hopkins University, Baltimore, MD, USA, University of Liverpool, Liverpool, UK, University of Cape Town, Cape Town, South Africa, were presented at CROI 2018. The study is the first to measure PK of once-daily TAF with RIF and compare it directly to tenofovir disoproxil fumarate (TDF).

TAF achieves lower plasma and higher intracellular tenofovir (TFV) concentrations than TDF, but it is a substrate of drug transporters so has potential for drug interactions, especially with inducers like RIF.

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A recent parallel design PK study showed when twice-daily TAF was given with RIF intracellular TFV-diphosphate (DP) decreased by 24% and plasma TAF by 15% compared with once-daily TAF alone.3,4

RIFT is a phase 1, open label, single arm, single centre evaluation in 23 HIV negative participants (21 completed). Participants received TAF/ FTC 25/200mg once daily (28 days) with food, followed by TAF/FTC + RIF 600mg once daily (28 days, RIF on empty stomach followed by TAF/ FTC with meal after 30 mins), followed by TDF 300mg once daily (28 days) with food.

Twenty-one participants completed all PK phases. Geometric mean ratios (GMR) for the main PK parameters are shown in Table 1.

Table 1: PK Once-Daily TAF + RIF vs TAF vs TDF

PK Parameter

TAF + RIF vs TAF
GMR (90% CI)

TAF + RIF vs TDF
GMR (90% CI)

Plasma TAF

Cmax ng/mL CV

0.50 (0.42-0.61)

AUC0-24 ng*h/mL CV

0.45 (0.33-0.60)

Plasma TFV

Cmax ng/mL CV

0.35 (0.30-0.42)

AUC0-24 ng*h/mL CV

0.46 (0.40-0.52)

C24h fmol*h/106 CV

0.45 (0.42-0.50)

Intracellular TFV-DP

Cmax ng/mL CV

0.62 (0.52-0.74)

0.23 (0.17-0.30)

AUC0-24 ng*h/mL CV

0.64 (0.54-0.75)

0.24 (0.18-0.32)

C24h fmol*h/106 CV

0.57 (0.47-0.71)

0.24 (0.18-0.32)

FTC-TP PK parameters were not affected by RIF. There were no significant associations with any polymorphisms.

There were two grade 3 adverse events and 2/23 participants discontinued: one case of transient hyper transaminitis during administration of TAF/FTC only (the investigators judged this to be unlikely drug related); one gastrointestinal symptoms (judged likely RIF-related).

The investigators concluded that although RIF co-administration decreased the plasma TAF by 55% and intracellular TFV-DP AUC by 36%, intracellular TFV-DP AUC were 76% higher with TAF + RIF than with TDF (300 mg once daily) alone.

Comment

These data support further evaluation of TAF + RIF in people with HIV and TB.

Unlike the previous TAF + RIF PK study, because of the comparison of intracellular TFV-DP concentrations with TAF + RIF to those with TDF alone, this evaluation suggests that doubling dose of TAF when coadministered with RIF is unnecessary.

This article was provided by HIV i-Base. It is a part of the publication The 25th Conference on Retroviruses and Opportunistic Infections. Visit HIV i-Base's website to find out more about their activities, publications and services.

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